Alzheimer's disease is a neurodegenerative disease which is pathologically characterized by formation of senile plaques and neurofibrillary tangles, together with neuronal degeneration and dropout. Alzheimer's disease causes symptoms of dementia in which memory, recognition, thinking, judgment and the like are progressively lost, thus finally leading to death. To the present, no method which is effective for prevention and treatment of this disease has been known.
A protein playing a major role in constituting senile plaques deposited in the brain is β-amyloid protein (amyloid β protein, Aβ), which consists of 39 to 43 amino acids. β-Amyloid protein has cytotoxicity, which is thought to cause Alzheimer's disease (Non-Patent Document 1). The β-amyloid protein which is secreted from cells is a polypeptide mostly consisting of 40 to 42 amino acids, and in particular, the β-amyloid protein consisting of 42 amino acids is known to be deposited in the brain in an early stage with stronger aggregability, and to have strong cytotoxicity (Non-Patent Document 2). Although the β-amyloid protein is ubiquitously produced in the body, the original function thereof has not been clarified.
β-amyloid protein is produced by processing of an amyloid precursor protein (APP), which is a transmembrane protein. Among the patients suffering from familial Alzheimer's disease, there are cases where mutation is recognized in the APP gene. Furthermore, it is known that in the cells transfected with this mutated APP gene, the amount of production/secretion of the β-amyloid protein is increased. From these, it is conceived that a medicament inhibiting the production/secretion of β-amyloid protein would be effective for the prevention or treatment of Alzheimer's disease.
With regard to the process for the cleavage of APP to β-amyloid protein, an aspartic protease such as BACE (β-site APP cleaving enzyme) (Non-Patent Document 3) or Asp1 (Non-Patent Document 4) is reported as the β-secretase associated with the N-terminal cleavage of the β-amyloid protein. Meanwhile, with regard to the γ-secretase which is responsible for the C-terminal cleavage, it is strongly suggested that Presenilin constitutes a part thereof (Non-Patent Document 5). There has been a report on the inhibitors of these β-secretases or γ-secretase (Non-Patent Document 6), and many of them are peptidic compounds.
Smith et al. disclose a compound in Patent Document 1, which has a sulfonamide skeleton, and regulates the production of β-amyloid protein. Belanger et al. also disclose a compound in Patent Document 2, which has a bicycloalkylsulfonamide skeleton, and inhibits γ-secretase. Furthermore, Patent Documents 3, 4 and 5 disclose compounds having an activity for inhibiting the production of β-amyloid protein. Patent Documents 6, 7 and 8 also disclose diarylsulfone compounds which inhibit γ-secretase. In addition, Patent Documents 9 and 10 also disclose compounds inhibiting the production of β-amyloid protein. Meanwhile, Patent Document 11 discloses a thionaphthalene derivative which inhibits the aggregation of amyloid proteins.    [Patent Document 1] International Publication No. WO 00/50391    [Patent Document 2] International Publication No. WO 01/70677    [Patent Document 3] International Publication No. WO 02/40451    [Patent Document 4] International Publication No. WO 02/40508    [Patent Document 5] International Publication No. WO 02/47671    [Patent Document 6] International Publication No. WO 02/081433    [Patent Document 7] International Publication No. WO 02/081435    [Patent Document 8] International Publication No. WO 03/018543    [Patent Document 9] International Publication No. WO 03/055850    [Patent Document 10] International Publication No. WO 05/000798    [Patent Document 11] Japanese Patent Application Laid-open No. 9-95444    [Non-Patent Document 1] Science, Vol. 259, p. 514 (1993)    [Non-Patent Document 2] Journal of Biological Chemistry, Vol. 270, p. 7013 (1995)    [Non-Patent Document 3] Science, Vol. 286, p. 735 (1999)    [Non-Patent Document 4] Molecular and Cellular Neuroscience, Vol. 16, p. 609 (2000)    [Non-Patent Document 5] Journal of Medicinal Chemistry, Vol. 44, p. 2039 (2001)